Oxazolidin-2-one derivatives

ABSTRACT

The 5-(piperidine-4-spiro)-oxazolidin-2-one derivatives of formula:   IN WHICH R is hydrogen, an alkyl radical or an aryl radical, R1 is an alkyl radical and R2 is hydrogen, or R1 and R2 form together a methylene or ethylene bridge, R3 is hydrogen or an alkyl radical and R4 is hydrogen, halogen, an alkoxy radical or a hydroxy radical, R, R2 and R4 not being simultaneously hydrogen, have analgesic and hypotensive properties.

[54] OXAZOLIDIN-Z-ONE DERIVATIVES [75] Inventor: Jacques G. Maillard,Paris, France [73] Assignee: Laboratoires Jacques Logeais,lssyles-Moulineaux, France [22] Filed: March 19, 1970 [21] Appl No.:21,188

[30] Foreign Application Priority Data March 25, 1969 France..-....6908662 52 us. or. ...260/293.62, 260/293.52, 260/293.66,

' 424/267 51 Int. Cl. ..C07d 99/04 53 Field of Search .,...260/294.3 B,293.62

56 References Cited UNITED STATES PATENTS 3,399,192 8/1968 Regnier etal. ..260/240 OTHER PUBLICATIONS C'ram-etaL, Organic Chemistry, 2nd Ed.,Mc-

Grawl'lill, New York, N.Y. (1964), pp. 376, 377 and PrimaryExaminer-John D. Randolph Assistant Examiner-G. Thomas ToddAttorney-Roberts, Cushman & Grover [57] ABSTRACT The5-(piperidine-4-spiro)-oxazolidin-2-one derivatives of formula:

s 27% 0-c0 011 16 I R1 CHNH I R R (I) in which R is hydrogen, an alkylradical or an'aryl radical, R isan alkyl radical and R is hydrogen, orR, and R form together a methylene-or ethylene bridge, R ishydrogen oran alkyl radical and R is hydrogen, halogen, analkoxy radical or ahydroxy radical, R, R

and R not being simultaneously hydrogen, have analgesic and hypotensiveproperties.

12 Claims, No Drawings OXAZOLIDIN-Z-ONE DERIVATIVES This inventionrelates to new oxazolidin-Z-one derivatives, to a process for theirpreparation and to their applications, particularly in therapeutics.

More particularly, the invention is concerned with(piperidine-4-spiro.)-oxazolidin-2-one derivatives of formula:

s 7 R (DH-NH R2 R in which R is hydrogen, or an alkyl or aryl radical, Ris an alkyl radical and R is hydrogen or else R, and R form together amethylene or ethylene bridge, R is hydrogen or an alkyl radical and R,is hydrogen, halogen, an alkoxy radical or a hydroxy radical, R, R and Rnot being simultaneously hydrogen, and their acid addition salts.

In the above definition, the alkyl radicals and the alkyl moieties ofthe alkoxy radicals are preferably lower radicals, having in particularone to six carbon atoms.

When R is halogen, it is advantageously chlorine,

bromine or fluorine, particularly chlorine.

Among the salts of derivatives (I) are included the addition saltsformed with hydrochloric, hydrobromic, maleic, lactic, tartaric acids,and the like.

These new derivatives exhibit pharmacological properties that make themtherapeutically useful.

The derivatives in which R, and R form together an ethylene bridge werefound particularly interesting, however, those having a methylene bridgeand those branched phenylaklyl side-chain are also active.

The invention relates also to the therapeutical application of such newderivatives, particularly as analgesic and hypotensive drugs, in theform of a composition comprising the active compound together with apharmaceutically administrable, vehicle.

The new derivatives according to the invention may be prepared bycondensing a ketone of formula:

with a (piperidine-4-spiro )-oxazolidinone of formula:

O-CO (IZIINII R (I II) R, R,,"R R and R, having the above definedmeanings, and reducing the resulting condensation product.

The process for the preparation of compounds (1) according to theinvention is illustrated'by the following reaction sequence:

Generally, condensation is carried out in an anhydroussolvent,'preferably in the presence of an acid,

under blocked form, for example as an alkoxy radical.

The following examples are given to illustrate the invention.

EXAMPLE 1 R 0 H, R,R =)2 5-( l ,2,3,4-tetrahydro-naphthalene-Z:spiro)-4-ethyl-oxazolidin-2-one.

Z-Tetralone (ll.l g; 0.069 mole) and 4- ethyl-5- R3 R4 H l-piperidine-4-(piperidine-4-spiro)-oxazolidin-2-one (6.8 g; 0.040

mole) are dissolved in xylene (200 ml) and boiled during 16 hours whileremoving the water formed. After evaporating the xylene, the residue isdissolved in ethanol (400 ml) and is then hydrogenated in the presenceof 5 percent palladium-over-charcoal, at normal pressure and at 50C,during 8 hours. After filtration of the catalyst, which is washed withhot acetic acid, the solvents are evaporated to dryness and the residueis taken up into a 2N ether-HCl mixture. The

acidic aqueous'phase is extracted twice with ether and is then madealkaline. The precipitate is then redissolved with normal HCI,decolorized over charcoal,-

precipitated again by alkalinization, dried and then purifled bydissolution in benzene and evaporation of the solvent to give 6 g of thedesired derivative. Yield: 48 percent. M.p.= 200C (instantaneous)Analysis: CygHggNgOz Calculated Found C 72.58 73.04 H 8.33 7.80

EXAMPLE 2 -(2,3-dihydroindene-Z ethyl-oxazolidin-Z-one.

Thisderivative is prepared as described in example 1; by heating2-indanone and 4-ethyl5-(piperidine-4- spiro)-oxazolidin-2-one intoluene, followed by catalytic hydrogenation. The product 'isrecrystallized from methanol. Yie1d: 70' percent. M.p. 254C(instantaneous).- Analysis: C gH N202 Calculated Found C 72.20 72.10 H7.74 8.43 N 9.36 9.33

EXAMPLE 3 5-( l ,2,3,4-tetrahydro-naphthalene-Z: l-piperidine-4-spiro)-oxazolidin-2-one This derivative is prepared as described inexample 1, by heating 2-tetralone and5-(piperidine-4-spiro)-oxazolidin-2-one in toluene, in the presence of asmall amount of p-toluenesulfonicacid, followed by cata-. lytichydrogenation. The product is recrystallized from isopropanol. M.p. 211C (instantaneous). Analysis: C nHgzNgQg v v Found 7 X7 Calculated C71.29 71.43 H 7.74 7.89 N 9.78 9.98

' EXAMPLE 4 s s :)z a"- 4 I: Calculated Found C 76.21 76.02 H 7.23 7.54N 7.73 7.70

EXAMPLE 5 R,=c,H, R,=CH R,=R,=R.=H

S-(phenyl-l -isopropyl-piperidine-4-spiro )-4-ethyl-oxazolidin-2-one.

This derivative is prepared as described in example 1, by heatingphenylacetone and 4-ethyl-5-(piperidine- 4-spiro)-oxazolidin-2-one intoluene, in the presence of a small amount of toluene sulfonic acid,followed by catalytic hydrogenation.

The product is recrystallized from dilute methanol, and then from ethylacetate. M.p. 174C (instantaneous).

Analysis: C .H, N,O,

- 5 1 -piperidine-4-spiro )-4- Calculated Found C 71.48 71.80 H 8.678.97 N 9.26 9.36

EXAMPLE 6 R ==CH R R==(CH R R =H M.p. 185-187C (instantaneous) Analysis:i

. i: Calculated Found C 71.97 71.88 H 8.05 8.12 N 9.33 9.28

EXAMPLE 7 R C H R,-R, (CH,), R H R OCH;, at 7-position M.p. 194CAnalysis Calculated Found C 69.74 69.7 H 8.19 8.0 N 8.13 8.0

EXAMPLE 8 R z s r' z 2): a F H I 4 OC,l-l,, at 7-position M.p. 165166CAnalysis 1: Calculated Found C 70.55 70.3 H 8.18 8.7 N 7.84 8.0

EXAMPLE 9 R a s 1 z 2): 3 H 4 OCH, at S-position M.p.= 238C Analysis 7Calculated Found C 69.74 69.7 H 8.19 8.5 N 8.13 8.2

EXAMPLE 10 R CgHs Il -R2 (CH2): R3 H R. Cl at 6-position M.p. 176C.Analysis:

% Calculated Found C 65.4 65.2 H 7.22 7.6 N 8.03 8.1 CI 10.16 10.6

EXAMPLE 1 1 R a s 1 2 2): 3 H 4 hydrochloride is purified by boilingwith 20 ml ethanol 5 and is then converted to a base at pH 7.3 in hotaqueous solution, after which is it suction filtered and dried.

M .p. 2109C. Analysis:

% 7 Calculated Found C 69.06 I 69.0 H 7.93 8.1 N 8.48 8.4

EXAMPLE l2 R=C2H5 R|R2 (CH2)z R3=CH3 R:

M.p. 185C Analysis:

% Calculated Found C 73.13 73.0 H 8.59 8.7 N 8.53 8.65

EXAMPLE 13 R C2H5 R Rz (CH2), 'R3-= "CaH- R4 M.p. 167C Analysis:

% Calculated Found C 74.11 73.8 H 9.05 9.2 N 7.86 7.8

EXAMPLE 14 R H R,R, CH, R nC l-1 R H M.p. 168C Analysis: 111 CalculatedFound C 72.8l 72.71 H 8.04 8.57 N 8.94 9.15

EXAMPLE 15 R=C2H5 R|=CH3 RQ=R3=H R4: OCl-l at meta-positionM.p.=117-119C Analysis:

% Calculated Found C 68.64 69.3 H 8.49 8.8 N 8.43 8.2

EXAMPLE 16 H 2): 3 H 7 4 C11 0 at 7-position M.p.=173-175C Analysis:

% Calculated Found C 68.34 68.60 H 7.65 7.81 N 8.86 8.84

Amount of 6 EXAMPLE 17 R s: 1 2 2): 3 H 4 C11 0 at 7-position M.p.=188-192C Analysis:

k Calculated Found Data obtained from pharmacological testsdemonstrating'the efficiency of the derivatives according to Amount ofderivative derivative from Example Protection from example 2 Protection1 rug/kg mg/kg The derivative from example 1 reduces the sensation ofthermal pain in mice placed on a metal plate heated at 55C (test ofEddy, Jacob and Blozowski, Arch. Int. Pharmac. 1961, 133, page 296). Onintraperitoneal administration at the rate of 30 mg/kg it provides 51percent protection. The derivative of example 2, ad-

ministered at the same dosage, provides 36 percent protection.

Other results of experiments carried out'on mice, according to themethods of Koster and Eddy, are given in Table 1 below.

in addition to their analgesic properties demonstrated above, thederivatives according to the invention have adrenolytic andhypotensiveproperties. Thus, the derivative from example 1 suppresses orreverses the hypertensive and vasoconstrictive action of adrenalin inrabbit, cat and dog at a dosage of 250 1.1g

per kg on intravenous administration or of 5 mglkg by the intraduodenalroute. I

Similarly, Table 11 below reports the results of similar tests conductedwith other derivatives of formula l).

TABLE n Adrenolytic action in dog active dosage 20 mg/kg [.D.

0.25mglkg IN.

10 mg/kg ID.

2 mg/kg l.V.

Product from Example No.

EXAMPLE 18 Tablets containing:

Product from example I I 0.10 g Starch, STA Rx [500 0.150 g EXAM PLE l9Drinkable drops, containing:

Product i'rom example I (as the hydrochloride) 0.05 g Glycerol 2 ccDistilled water qJ. to make cc EX- KMPLE 20 lnjectable solution inampoules containing:

Product from example 3 (u the hydrochloride) 0.03 g Phyliological salinesolution to l0 cc EXAMPLE 21 Suppository containing: a Product fromexample 7 0.05 g Excipient based on hydrogenated fatty acid esters, q.s.to make. I suppository it is apparent from the above that thederivatives according to the invention are therapeutically useful by aany of the usual routes of administration. Depending on the product, 20to 1000 mg of active ingredient, optionall y combined with a convenientvehicle for the route of administration selected, will be administeredper 24 hours. It is to be noted that the acid addition salts of thederivatives according to the invention are very simply obtained, bydissolution of the derivatives in an acid, for example in one equivalentof hydrochloric acid, .and that they are soluble. Therefore, the drugmay readily be administered in liquid form.

Having now described my invention what I claim as new and desire tosecure by Letters Patent is:

l. A compound selected from A) 5-(piperidine-4-' spiro)-oxazolidin-2-one derivatives of formula:

II-N R CII-NII in which R is selected from the group consisting ofhydrogen, the lower alkyl radicals and phenyl, n is an integer selectedfrom 1 and 2, R -is selected from the group consisting of hydrogen andthe lower alkyl radicals and R,is selected from the group consisting ofhydrogen, chlorine, bromine, fluorine, the lower alkoxyradicals and thehydroxy radical, and B) their acid addition salts.

2. 5-( l,2,3,4-tetrahydro-naphthalene-2: l -piperidine- 4-spiro )-4-phenyl oxazolidimZ-one and its acid addition salts.

3. 5-(2,3-dihydro-indene-2: l -piperidine-4-spiro )-4-ethyl-oxazolidin-Z-one and its acid addition salts.

4'. 5 l ,2,3,4-tetrahydro-naphthalene-2: l -piperidine-4-apiro)-4-methyl oxazolidin-2-one and its acid addition salts. I

2: l -piperidine-4-spiro )-4-ethyl-oxazolidin-Z-one and Y its acidaddition salts.

6. 5-( l-n-propyl-l ,2,3-,4-tetrahydronaphthalene-Z: lpiperidinei-spiro)-4-ethyl-oxazolidin-2-one and its acid addition salts.

7. A compound as claimed in claim 1, wherein n is 2. i 8. A compound asclaimed in claim 1, wherein R is 5-( S-methoxy-l ,2,3,4-tetrahydro-naphtha-lene-

2. 5-(1,2,3,4-tetrahydro-naphthalene-2:1-piperidine-4-spiro)-4-phenyloxazolidin-2-one and its acid addition salts. 3.5-(2,3-dihydro-indene-2:1-piperidine-4-spiro)-4-ethyl-oxazolidin-2-oneand its acid addition salts. 4.5-(1,2,3,4-tetrahydro-naphthalene-2:1-piperidine-4-spiro)-4-methyl-oxazolidin-2-one and its acid addition salts. 5.5-(5-methoxy-1,2,3,4-tetrahydro-naphtha-lene-2:1-piperidine-4-spiro)-4-ethyl-oxazolidin-2-oneand its acid addition salts. 6.5-(1-n-propyl-1,2,3,4-tetrahydronaphthalene-2:1-piperidine-4-spiro)-4-ethyl-oxazolidin-2-one and its acid addition salts.
 7. A compound as claimedin claim 1, wherein n is
 2. 8. A compound as claimed in claim 1, whereinR4 is chlorine. 9.5-(1,2,3,4-Tetrahydro-naphthalene-2:1-piperidine-4-spiro)-4-ethyl-oxazolidin-2-oneand its acid addition salts. 10.5-(1,2,3,4-Tetrahydro-naphthalene-2:1-piperidine-4-spiro)-oxazolidin-2-oneand its acid addition salts. 11.5-(7-methoxy-1,2,3,4-tetrahydro-naphthalene-2:1-piperidine-4-spiro)-4-ethyl-oxazolidin-2-one and its acid addition salts. 12.5-(6-Chloro-1,2,3,4-tetrahydro-naphthalene-2:1-piperidine-4-spiro)-4-ethyl-oxazolidin-2-one and its acid addition salts.